The FIRST and ONLY FDA-APPROVED botulinum toxin for the treatment of LOWER LIMB SPASTICITY in pediatric patients 2 years of age and older 1.

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1 The FIRST and ONLY FDA-APPROVED botulinum toxin for the treatment of LOWER LIMB SPASTICITY in pediatric patients years of age and older 5 Steps to dosing and dilution with Indication is indicated for the treatment of lower limb spasticity in pediatric patients years of age and older. The safety and effectiveness of injected into upper limb muscles or proximal muscles of the lower limb for the treatment of spasticity in pediatric patients has not been established. Safety and effectiveness in pediatric patients with lower limb spasticity below years of age have not been evaluated. Safety and effectiveness in pediatric patients with cervical dystonia or upper limb spasticity have not been established. Important Safety Information Warning: Distant Spread of Toxin Effect Postmarketing reports indicate that the effects of and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including upper limb spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to lower than the maximum recommended total dose. Please see additional Important Safety Information throughout this brochure, and accompanying Full Prescribing Information.

2 For pediatric patients with lower limb spasticity years of age and older offers FDA-approved dosing recommendations Botulinum toxins (BoNTs) are not interchangeable and the potency units are not the same. Units of biological activity of cannot be compared to, or converted into, units of any other BoNT. Step : Obtain your patient s weight Dosing is based on Units per kilogram of body weight. Convert from pounds to kilograms ( kg is equal to. lb) Step : Choose unilateral or bilateral lower limb injection Recommended total dose per treatment session: Unilateral to 5 Units/kg with a total dose not to exceed 5 Units/kg or, Units, whichever is lower Bilateral to Units/kg with a total dose not to exceed Units/kg or, Units, whichever is lower Step : Select muscles (gastrocnemius/ soleus) The total dose administered should be divided between the affected spastic muscles of the lower limb(s). When possible, the dose should be divided across more than injection site in any single muscle No more than.5 ml should generally be administered at any single injection site Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, eg, ultrasound, electromyography, or electrical stimulation, is recommended to target the injection sites Important Safety Information (continued) Contraindications is contraindicated in patients with known hypersensitivity to any botulinum toxin preparation or to any of the components; or in the presence of infection at the proposed injection site(s); or in patients known to be allergic to cow s milk protein. Hypersensitivity reactions including anaphylaxis have been reported. Please see additional Important Safety Information throughout this brochure, including Boxed Warning regarding distant spread of toxin effect, and accompanying Full Prescribing Information. Step 4: Determine dose Recommended dose range per muscle, per leg, of the GSC* Gastrocnemius 6-9 Units/kg/leg Total dose divided in up to 4 injection sites Soleus 4-6 Units/kg/leg Total dose divided in up to injection sites No more than.5 ml should generally be administered at any single injection site. *Gastroc-soleus complex. Do not exceed 5 Units/kg total dose for unilateral injection, or Units/kg for bilateral injection, or, Units, whichever is lower. Dosing in initial and subsequent treatment sessions should be tailored to the individual based on Size, number, and location of muscles involved Severity of spasticity Presence of local muscle weakness Patient s response to previous treatment and/or Adverse event history with botulinum toxin Retreatment The majority of patients in the clinical study were retreated between 6 and weeks; however, some had a longer duration of response The degree and pattern of muscle spasticity and overall clinical benefit at the time of re-injection may necessitate alterations in the dose of and the muscles to be injected

3 For pediatric patients with lower limb spasticity years of age and older dilution and reconstitution Step 5: Achieve desired concentration Considerations for achieving desired concentration include: patient weight, limit of.5 ml per injection site, and recommended number of injection sites per muscle in the GSC Total dose per treatment session Lower limb: unilateral, not to exceed 5 Units/kg; bilateral, not to exceed Units/kg, or, Units, whichever is lower -Unit Vial 5-Unit Vial.5 ml of Diluent*.5 ml of Diluent* Other dilutions may be necessary to enable dosing flexibility, for example: Diluent* per -Unit Vial Resulting Dose Diluent* per 5-Unit Vial Resulting Dose Units/. ml Resulting Dose Units/. ml Resulting Dose.6 ml 5 Units/. ml ml 5 Units/. ml Adapted from Section., Table of the Full Prescribing Information. * Sterile preservative-free.9 Sodium Chloride Injection, USP. Reconstituted is for intramuscular injection only. Reconstitution and injection checklist Using a sterile syringe, needle, and aseptic technique, draw up the appropriate amount of diluent. Insert the needle into the (abobotulinumtoxina) vial. The partial vacuum will begin to pull the diluent into the vial. Do not use the vial if no vacuum is observed. Swirl gently to dissolve. The reconstituted solution should be clear, colorless, and free of particulate matter. Draw the required patient dose of into a sterile syringe and dilute with additional diluent, if required, to achieve the final volume for injection. Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach an appropriately sized new sterile needle to administer the injection. Inject into target muscle(s) within 4 hours of reconstitution. should be used for only one injection session and for only one patient after reconstitution. After reconstitution, should be used for only one injection session and for only one patient. Once reconstituted, should be stored in the original container, in a refrigerator at C to 8 C (6 F to 46 F), protected from light, for up to 4 hours. It must be discarded if not used within 4 hours. Do not freeze reconstituted. Discard the vial and needle in accordance with local regulations. Important Safety Information (continued) Warnings and Precautions Lack of Interchangeability Between Botulinum Toxin Products The potency Units of are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products, and, therefore, units of biological activity of cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method. Please see additional Important Safety Information throughout this brochure, including Boxed Warning regarding distant spread of toxin effect, and accompanying Full Prescribing Information. 4 5

4 For pediatric patients with lower limb spasticity years of age and older dosing scenarios * Step : Obtain weight Step : Choose unilateral or bilateral lower limb injection Step : Select muscles Step 4: Determine dose (kg x [ Units/kg]) Eric, age John, age kg ( lb) kg (7 lb) Bilateral ( to Units/kg) Gastrocnemius Recommended dose range to 8 Units/kg Soleus Recommended dose range 8 to Units/kg Total Dose per Treatment Session to Units divided between affected spastic muscles Dose range for Gastrocnemius to 8 Units Dose range for Soleus 8 to Units Unilateral ( to 5 Units/kg) Gastrocnemius Recommended dose range 6 to 9 Units/kg Soleus Recommended dose range 4 to 6 Units/kg Total Dose per Treatment Session to 48 Units divided between affected spastic muscles Dose range for Gastrocnemius 9 to 88 Units Dose range for Soleus 8 to 9 Units Important Safety Information (continued) Warnings and Precautions (continued) Dysphagia and Breathing Difficulties Treatment with (abobotulinumtoxina) and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant side effects occur, additional respiratory muscles may be involved (see Boxed Warning). Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several weeks, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised. Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech, or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin. Pre-existing Neuromuscular Disorders Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junction disorders (eg, myasthenia gravis or Lambert-Eaton syndrome) should be monitored particularly closely when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including severe dysphagia and respiratory compromise from typical doses of. Step 5: Achieve desired concentration Vial Units Diluent.5 ml Resulting Dose Units/. ml Vial 5 Units Diluent.5 ml Resulting Dose Units/. ml *Hypothetical patient examples. Do not exceed 5 Units/kg total dose for unilateral injection, or Units/kg for bilateral injection, or, Units, whichever is lower. Sterile preservative-free.9 Sodium Chloride Injection, USP. Reconstituted is for intramuscular injection only. Please see additional Important Safety Information throughout this brochure, including Boxed Warning regarding distant spread of toxin effect, and accompanying Full Prescribing Information. 6 7

5 Important Safety Information (continued) Warnings and Precautions (continued) Human Albumin and Transmission of Viral Diseases This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vcjd). There is a theoretical risk for transmission of Creutzfeldt- Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vcjd have ever been identified for licensed albumin or albumin contained in other licensed products Intradermal Immune Reaction The possibility of an immune reaction when injected intradermally is unknown. The safety of (abobotulinumtoxina) for the treatment of hyperhidrosis has not been established. is approved only for intramuscular injection. Adverse Reactions Most common adverse reactions ( in any group and greater than placebo) in pediatric patients with lower limb spasticity for Units/kg, 5 Units/kg, Units/kg, or Units/kg; and, respectively, were: upper respiratory tract infection (9,, 5,, ), nasopharyngitis (9,,6,, 5), influenza (,, 4,, 8), pharyngitis (5,,,, 8), cough (7, 6, 4,, 6), and pyrexia (7,, 8, 7, 5). Drug Interactions Co-administration of and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curarelike agents), or muscle relaxants, should be observed closely because the effect of botulinum toxin may be potentiated. Use of anticholinergic drugs after administration of may potentiate systemic anticholinergic effects such as blurred vision. The effect of administering different botulinum neurotoxins at the same time or within several months of each other is unknown. Excessive weakness may be exacerbated by another administration of botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of. Please see additional Important Safety Information throughout this brochure, including Boxed Warning regarding distant spread of toxin effect, and accompanying Full Prescribing Information. 8 Use in Pregnancy Based on animal data may cause fetal harm. There are no adequate and well-controlled studies in pregnant women. should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pediatric Use Based on animal data may cause atrophy of injected and adjacent muscles; decreased bone growth, length, and mineral content; delayed sexual maturation; and decreased fertility. Geriatric Use In general, elderly patients should be observed to evaluate their tolerability of, due to the greater frequency of concomitant disease and other drug therapy. Subjects aged 65 years and over who were treated with for lower limb spasticity reported a greater percentage of fall and asthenia as compared to those younger ( versus 6 and 4 versus, respectively). To report SUSPECTED ADVERSE REACTIONS or product complaints, contact Ipsen at You may also report SUSPECTED ADVERSE REACTIONS to the FDA at -8-FDA-88 or 9

6 Pediatric Lower Limb Spasticity Dosing Tool Weight (kg) Unilateral: Total dose per treatment session ( to 5 Units/kg/leg) Gastrocnemius (6 to 9 Units/kg/leg) Soleus (4 to 6 Units/kg/leg) Unilateral dose range per muscle Recommended total dose per treatment session: Unilateral to 5 Units/kg with a total dose not to exceed 5 Units/kg or, Units, whichever is lower Bilateral to Units/kg with a total dose not to exceed Units/kg or, Units, whichever is lower : The FIRST and ONLY FDA-APPROVED botulinum toxin for the treatment of LOWER LIMB SPASTICITY in pediatric patients years of age and older Step : Obtain your patient s weight Step : Choose unilateral or bilateral lower limb injection Step : Select muscles (gastrocnemius/soleus) Step 4: Determine dose Step 5: Achieve desired concentration * Sterile preservative-free.9 Sodium Chloride Injection, USP. Reconstituted is for intramuscular injection only. See pages through 4 for detailed information on dosing and dilution. Important Safety Information (continued) and all botulinum toxin products have a Boxed Warning which states that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism. Those symptoms include swallowing and breathing difficulties that can be life-threatening. Please see additional Important Safety Information throughout this brochure, including Boxed Warning regarding distant spread of toxin effect, and accompanying Full Prescribing Information. Reference:. (abobotulinumtoxina) [Prescribing Information]. Basking Ridge, NJ: Ipsen Biopharmaceuticals, Inc; June 7. (abobotulinumtoxina) for injection, for intramuscular use - and 5-Unit vials. DYSPORT is a registered trademark of Ipsen Biopharm Limited. 7 Ipsen Biopharmaceuticals, Inc. August 7 DYS-US-5

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8 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DYSPORT safely and effectively. See full prescribing information for DYSPORT. for injection, for intramuscular use Initial U.S. Approval: 9 WARNING: DISTANT SPREAD OF TOXIN EFFECT See full prescribing information for complete boxed warning The effects of DYSPORT and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms RECENT MAJOR CHANGES Indications and Usage, Spasticity in Adults (.) 6/7 Indications and Usage, Pediatric Lower Limb Spasticity (.4) 7/6 Dosage and Administration, Spasticity in Adults (.4) 6/7 Dosage and Administration, Pediatric Lower Limb Spasticity (.5) 7/ INDICATIONS AND USAGE DYSPORT is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for: The treatment of adults with cervical dystonia (.) The temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients < 65 years of age (.) The treatment of spasticity in adults (.) The treatment of lower limb spasticity in pediatric patients years of age and older (.4) DOSAGE AND ADMINISTRATION Instructions for Safe Use (.) Once reconstituted, store in original container in a refrigerator at C to 8 C (6 F to 46 F) and use within 4 hours (.) Do not freeze after reconstitution (.) Protect from light (6) Reconstitution instructions are specific for the Unit and 5 Unit vials (.) Reconstituted DYSPORT is intended for intramuscular injection only. After reconstitution, DYSPORT should be used for only one injection session and for only one patient. Cervical Dystonia (.) Initial dose is 5 Units given intramuscularly as a divided dose among the affected muscles Re-treatment every to 6 weeks or longer, as necessary, based on return of clinical symptoms with doses administered between 5 Units and Units to optimize clinical benefit Re-treatment should not occur in intervals of less than weeks Titrate in 5 Unit steps according to patient s response Glabellar Lines (.) Administer a total dose of 5 Units, divided in five equal aliquots of Units each, intramuscularly to affected muscles to achieve clinical effect Re-treatment should be administered no more frequently than every months Spasticity in Adults (.4) Select dose based on muscles affected, severity of muscle spasticity, prior response and adverse reaction history following treatment with DYSPORT or other botulinum toxin A Dosing for upper limb spasticity: between 5 Units and Units Dosing for lower limb spasticity: up to 5 Units The maximum recommended total dose per treatment session (upper and lower limb combined) in adults is 5 Units Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than weeks Pediatric Lower Limb Spasticity (.5) Select dose based on the affected muscle, severity of spasticity, and treatment history with botulinum toxins Dosing is based on Units/kg; recommended total DYSPORT dose per treatment session is to 5 Units/kg per limb FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: DISTANT SPREAD OF TOXIN EFFECT INDICATIONS AND USAGE. Cervical Dystonia. Glabellar Lines. Spasticity in Adults.4 Lower Limb Spasticity in Pediatric Patients DOSAGE AND ADMINISTRATION. Instructions for Safe Use. Dosing in Cervical Dystonia. Dosing in Glabellar Lines.4 Dosing in Spasticity in Adults.5 Dosing in Lower Limb Spasticity in Pediatric Patients DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5. Lack of Interchangeability Between Botulinum Toxin Products 5. Spread of Toxin Effect 5. Dysphagia and Breathing Difficulties 5.4 Facial Anatomy in the Treatment of Glabellar Lines 5.5 Pre-existing Neuromuscular Disorders 5.6 Human Albumin and Transmission of Viral Diseases 5.7 Intradermal Immune Reaction 6 ADVERSE REACTIONS 6. Clinical Trials Experience 6. Postmarketing Experience 6. Immunogenicity Total dose per treatment session must not exceed 5 Units/kg for unilateral lower limb injections, Units/kg for bilateral injections, or units, whichever is lower Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than weeks DOSAGE FORMS AND STRENGTHS For Injection: Units or 5 Units lyophilized powder in a single-use vial for reconstitution with preservative-free.9 Sodium Chloride Injection, USP () CONTRAINDICATIONS Hypersensitivity to any botulinum toxin product or excipients (4, 6., 6.) Allergy to cow s milk protein (4) Infection at the proposed injection site(s) (4) WARNINGS AND PRECAUTIONS The potency Units of DYSPORT are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of DYSPORT cannot be compared to or converted into units of any other botulinum toxin products (5.) Recommended dose and frequency of administration should not be exceeded (5.4) Immediate medical attention may be required in cases of respiratory, speech or swallowing difficulties (5.) Concomitant neuromuscular disorder may exacerbate clinical effects of treatment (5.5) DYSPORT contains human albumin. There is a risk for transmission of Creutzfeldt-Jakob disease (CJD) however, no cases of transmission of viral diseases or CJD have ever been identified for albumin (5.6) ADVERSE REACTIONS Cervical Dystonia Most commonly observed adverse reactions ( 5 of patients) are: muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, musculoskeletal pain, dysphonia, injection site pain and eye disorders (6.) Glabellar Lines The most frequently reported adverse reactions ( ) are: nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, nausea, and blood present in urine (6.) Spasticity in Adults Upper limb spasticity: The most frequently reported adverse reactions (>) are: urinary tract infection, nasopharyngitis, muscular weakness, musculoskeletal pain, dizziness, fall and depression (6.) Lower limb spasticity The most frequently reported adverse reactions ( 5) are: falls, muscular weakness, and pain in extremity (6.) Lower Limb Spasticity in Pediatric Patients The most frequently reported adverse reactions ( ) are: upper respiratory tract infection, nasopharyngitis, influenza, pharyngitis, cough and pyrexia (6.) To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at or FDA at -8-FDA-88 or DRUG INTERACTIONS Concomitant use of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents), or muscle relaxants, should be observed closely because the effect of botulinum toxin may be potentiated (7) Anticholinergic drugs may potentiate systemic anticholinergic effects (7) The effect of administering different botulinum neurotoxins during the course of treatment with DYSPORT is unknown (7) USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.) Administer DYSPORT with care in elderly patients, reflecting the greater frequency of concomitant disease and other drug therapy (8.5) See 7 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 9/7 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8. Pregnancy 8. Lactation 8. Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Ethnic Groups OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mechanism of Action. Pharmacodynamics. Pharmacokinetics NONCLINICAL TOXICOLOGY. Carcinogenesis, Mutagenesis, Impairment of Fertility 4 CLINICAL STUDIES 4. Cervical Dystonia 4. Glabellar Lines 4. Spasticity in Adults 4.4 Pediatric Patients with Lower Limb Spasticity 6 HOW SUPPLIED/STORAGE AND HANDLING 7 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

9 FULL PRESCRIBING INFORMATION WARNING: DISTANT SPREAD OF TOXIN EFFECT Postmarketing reports indicate that the effects of DYSPORT and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including upper limb spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to or lower than the maximum recommended total dose [see Warnings and Precautions (5.)]. INDICATIONS AND USAGE. Cervical Dystonia DYSPORT is indicated for the treatment of adults with cervical dystonia.. Glabellar Lines DYSPORT is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients less than 65 years of age.. Spasticity in Adults DYSPORT is indicated for the treatment of spasticity in adult patients..4 Lower Limb Spasticity in Pediatric Patients DYSPORT is indicated for the treatment of lower limb spasticity in pediatric patients years of age and older. DOSAGE AND ADMINISTRATION. Instructions for Safe Use The potency Units of DYSPORT are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of DYSPORT cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method [see Description ()]. Reconstituted DYSPORT is intended for intramuscular injection only. Reconstitution instructions are specific for each of the Unit vial and the 5 Unit vial. These volumes yield concentrations specific for the use for each indication (Table ). Table : Dilution Instructions for DYSPORT Vials (5 Units and Units) Diluent* per 5 Unit Vial Resulting Dose Units per. ml Diluent* per Unit Vial Resulting Dose Units per. ml ml 5 Units.6 ml 5 Units ml 5 Units ml Units.5 ml Units ml Units 5 ml** Units ml Units *Preservative-free.9 Sodium Chloride Injection, USP Only Note: These dilutions are calculated for an injection volume of. ml. A decrease or increase in the DYSPORT dose is also possible by administering a smaller or larger injection volume (i.e..5 ml (5 decrease in dose),.8 ml ( decrease in dose) or.5 ml (5 increase in dose). ** When using 5 ml of diluent for a 5 Unit vial of DYSPORT, complete the following steps (see also.4 Dosing in Upper Limb Spasticity).. Reconstitute a 5 Unit vial of DYSPORT with.5 ml of Preservative-free.9 Sodium Chloride Injection, USP, gently mix, and set the vial aside.. Withdraw.5 ml of Preservative-free.9 Sodium Chloride Injection, USP, into a 5 ml syringe.. Take the 5 ml syringe with.5 ml Preservative-free.9 Sodium Chloride Injection, USP, and draw up the DYSPORT solution from the reconstituted vial without inverting and mix gently. The resulting concentration will be units/. ml. 4. Use immediately after reconstitution in the syringe. Dispose of any unused saline. After reconstitution, DYSPORT should be used for only one injection session and for only one patient. Once reconstituted, DYSPORT should be stored in the original container, in a refrigerator at C to 8 C (6 F to 46 F), protected from light for up to 4 hours. It must be discarded if not used within 4 hours. Do not freeze reconstituted DYSPORT. Discard the vial and needle in accordance with local regulations.. Dosing in Cervical Dystonia The recommended initial dose of DYSPORT for the treatment of cervical dystonia is 5 Units given intramuscularly as a divided dose among affected muscles in patients with or without a history of prior treatment with botulinum toxin. (A description of the average DYSPORT dose and percentage of total dose injected into specific muscles in the pivotal clinical trials can be found in Table of Section 4., Clinical Studies Cervical Dystonia.). Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Clinical studies with DYSPORT in cervical dystonia suggest that the peak effect occurs between two and four weeks after injection. Simultaneous EMG-guided application of DYSPORT may be helpful in locating active muscles. Dose Modification Where dose modification is necessary for the treatment of cervical dystonia, uncontrolled open-label studies suggest that dose adjustment can be made in 5 Unit steps according to the individual patient s response, with re-treatment every weeks or longer, as necessary, based on return of clinical symptoms. Uncontrolled open-label studies also suggest that the total dose administered in a single treatment should be between 5 Units and Units. Re-treatment, if needed, should not occur in intervals of less than weeks. Doses above Units have not been systematically evaluated. Special Populations Adults and elderly The starting dose of 5 Units recommended for cervical dystonia is applicable to adults of all ages [see Use in Specific Populations (8.5)]. Pediatric Patients The safety and effectiveness of DYSPORT in the treatment in pediatric patients less than 8 years of age has not been assessed [see Warnings and Precautions (5.)]. Instructions for Preparation and Administration for the Treatment of Cervical Dystonia DYSPORT is supplied as a single-use vial. Only use sterile preservative-free.9 Sodium Chloride Injection, USP for reconstitution of DYSPORT. Each 5 Unit vial of DYSPORT is to be reconstituted with ml of preservative-free.9 Sodium Chloride Injection USP to yield a solution of 5 Units per. ml or reconstituted with ml of preservative-free.9 Sodium Chloride Injection USP to yield a solution of 5 Units per. ml. Each Unit vial of DYSPORT is to be reconstituted with.6 ml of preservative-free.9 Sodium Chloride Injection USP to yield a solution equivalent to 5 Units per. ml. Using an appropriately sized sterile syringe, needle and aseptic technique, draw up ml or ml of sterile, preservative-free.9 Sodium Chloride Injection USP for the 5 Unit vial or.6 ml of sterile, preservative-free.9 Sodium Chloride Injection USP for the Unit vial. Insert the needle into the DYSPORT vial. The partial vacuum will begin to pull the saline into the vial. Any remaining required saline should be expressed into the vial manually. Do not use the vial if no vacuum is observed. Swirl gently to dissolve. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted DYSPORT should be a clear, colorless solution, free of particulate matter, otherwise it should not be injected. Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach an appropriately sized new sterile needle. Discard the vial and needle in accordance with local regulations.. Dosing in Glabellar Lines The dose of DYSPORT for the treatment of glabellar lines is a total of 5 Units given intramuscularly in five equal aliquots of Units each to achieve clinical effect (see Figure ). Special Populations Adults A total dose of 5 Units of DYSPORT, in five equal aliquots, should be administered to achieve clinical effect. The clinical effect of DYSPORT may last up to four months. Repeat dose clinical studies demonstrated continued efficacy with up to four repeated administrations. It should be administered no more frequently than every three months. When used for re-treatment, DYSPORT should be reconstituted and injected using the same techniques as the initial treatment. Pediatric Patients DYSPORT for glabellar lines is not recommended for use in pediatric patients less than 8 years of age [see Warnings and Precautions (5.)]. Instructions for Preparation and Administration for the Treatment of Glabellar Lines DYSPORT is supplied as a single-use vial. Only use sterile preservative-free.9 Sodium Chloride Injection, USP for reconstitution of DYSPORT. Each Unit vial of DYSPORT is to be reconstituted with.5 ml of preservative-free.9 Sodium Chloride Injection USP prior to injection. The concentration of the resulting solution will be Units per.8 ml ( Units per. ml) to be delivered in five equally divided aliquots of.8 ml each. DYSPORT may also be reconstituted with.5 ml of preservative-free.9 Sodium Chloride Injection USP for a solution of Units per.5 ml ( Units per. ml) to be delivered in five equally divided aliquots of.5 ml each. Using an appropriately sized sterile syringe, needle and aseptic technique, draw up.5 ml or.5 ml of preservative-free.9 Sodium Chloride Injection USP Insert the needle into the DYSPORT vial. The partial vacuum will begin to pull the saline into the vial. Any remaining required saline should be expressed into the vial manually. Do not use the vial if no vacuum is observed. Swirl gently to dissolve. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted DYSPORT should be a clear, colorless solution, free of particulate matter otherwise it should not be injected. Draw a single patient dose of DYSPORT into a sterile syringe. Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach a gauge needle. Discard the vial and needle in accordance with local regulations. Injection Technique Glabellar facial lines arise from the activity of the lateral corrugator and vertical procerus muscles. These can be readily identified by palpating the tensed muscle mass while having the patient frown. The corrugator depresses the skin creating a furrowed vertical line surrounded by tensed muscle (i.e., frown lines). The location, size, and use of the muscles vary markedly among individuals. Physicians administering DYSPORT must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. Risk of ptosis can be mitigated by careful examination of the upper lid for separation or weakness of the levator palpebrae muscle (true ptosis), identification of lash ptosis, and evaluation of the range of lid excursion while manually depressing the frontalis to assess compensation.

10 DYSPORT (abobotulinumtoxina) DYSPORT (abobotulinumtoxina) In order to reduce the complication of ptosis, the following steps should be taken: Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. Medial corrugator injections should be placed at least centimeter above the bony supraorbital ridge. Ensure the injected volume/dose is accurate and where feasible kept to a minimum. Do not inject toxin closer than centimeter above the central eyebrow. To inject DYSPORT, advance the needle through the skin into the underlying muscle while applying finger pressure on the superior medial orbital rim. Inject patients with a total of 5 Units in five equally divided aliquots. Using a gauge needle, inject Units of DYSPORT into each of five sites, two in each corrugator muscle, and one in the procerus muscle (see Figure ). Figure Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished, but no sooner than weeks after the previous injection. A majority of patients in clinical studies were retreated between -6 weeks; however some patients had a longer duration of response, i.e. weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. Clinical improvement may be expected one week after administration of DYSPORT. Lower Limb Spasticity In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of lower limb spasticity in adults [see Clinical Studies (4.)], doses of Units and 5 Units were divided among selected muscles at a given treatment session (see Table and Figure ). Table : DYSPORT Dosing by Muscle for Lower Limb Spasticity in Adults Muscles Injected Recommended Dysport Dose Recommended Number of Injection Sites per Muscle Distal Muscles Gastrocnemius.4 Dosing in Spasticity in Adults Dosing in initial and subsequent treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient s response to previous treatment, and/or adverse event history with botulinum toxins. No more than ml should generally be administered at any single injection site. The maximum recommended total dose (upper and lower limb combined) of DYSPORT for the treatment of spasticity in adults is 5 Units. Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique e.g., electromyography, electrical stimulation is recommended to target the injection sites. Upper Limb Spasticity In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of upper limb spasticity in adults [see Clinical studies (4.)], doses of 5 Units and Units were divided among selected muscles at a given treatment session (see Table and Figure ). Medial head Units to5 Units Lateral head Units to 5 Units Soleus Units to 5 Units Tibialis posterior Units to Units Flexor digitorum longus Units to Units to Flexor hallucis longus 7 Units to Units Figure : Muscles for Injection for Lower Limb Spasticity in Adults Table : DYSPORT Dosing by Muscle for Upper Limb Spasticity in Adult Patients Muscles Injected Recommended Dose DYSPORT Recommended Number of Injection(s) per Muscle Flexor carpi radialis (FCR) Units to Units to Flexor carpi ulnaris (FCU) Units to Units to Flexor digitorum profundus (FDP) Units to Units to Flexor digitorum superficialis (FDS) Units to Units to Brachialis Units to 4 Units to Brachioradialis Units to Units to Biceps Brachii (BB) Units to 4 Units to Pronator Teres Units to Units Figure : Muscles for Injection for Upper Limb Spasticity in Adults Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished, but no sooner than weeks after the previous injection. A majority of patients in clinical studies were retreated between -6 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. Instructions for Preparation and Administration for the Treatment of Spasticity in Adults DYSPORT is supplied as a single-use vial. Only use sterile preservative-free.9 Sodium Chloride Injection, USP for reconstitution of DYSPORT. The recommended concentration is Units/mL or Units/mL with preservative-free.9 Sodium Chloride Injection USP) (see Table ). Using an appropriately sized sterile syringe, needle and aseptic technique, draw up the required volume (Table ) of preservative-free.9 Sodium Chloride Injection USP. Insert the needle into the DYSPORT vial. The partial vacuum will begin to pull the saline into the vial. No more than.5 ml of saline should be introduced into the vial (see footnote in Table ). Do not use the vial if a vacuum is absent. Gently swirl to dissolve. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted DYSPORT should be a clear, colorless solution, free of particulate matter; otherwise it should not be injected. Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach an appropriately sized new sterile needle. Discard the vial and needle in accordance with local regulations.

11 .5 Dosing in Lower Limb Spasticity in Pediatric Patients Lower Limb Spasticity in Pediatric Patients years of age and older DYSPORT dosing for pediatric lower limb spasticity is based on Units per kilogram of body weight. Table 4 describes the recommended Units/kg dose of DYSPORT per muscle of the Gastrocnemius-Soleus Complex (GSC). The recommended total DYSPORT dose per treatment session is to 5 Units/kg for unilateral lower limb injections or to Units/kg for bilateral lower limb injections. However, the total dose of DYSPORT administered per treatment session must not exceed 5 Units/kg for unilateral lower limb injections or Units/kg for bilateral lower limb injections or units, whichever is lower. The total dose administered should be divided between the affected spastic muscles of the lower limb(s). When possible, the dose should be distributed across more than injection site in any single muscle (see Table 4). No more than.5 ml of DYSPORT should be administered in any single injection site. Dosing in initial and sequential treatment sessions should be tailored to the individual patient based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient s response to previous treatment, and/or adverse event history with botulinum toxins. Table 4: DYSPORT Dosing by Muscle for Lower Limb Spasticity in Pediatric Patients Muscle Injected Recommended DYSPORT Dose Range per muscle per leg (Units/kg Body Weight) Recommended number of injections per muscle Gastrocnemius 6 to 9 Units/kg a Up to 4 Soleus 4 to 6 Units/kg a Up to Total to 5 Units/kg divided across both muscles Up to 6 Note: a the listed individual doses to be injected in the muscles can be used within the range mentioned without exceeding 5 Units/kg total dose for unilateral injection or Units/kg for bilateral injections or Units whichever is lower. Figure 4: Muscles for Injection for Lower Limb Spasticity in Pediatric Patients Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, e.g. electromyography or electrical stimulation, is recommended to target the injection sites. Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished but no sooner than weeks after the previous injection. A majority of patients in the clinical studies were retreated between 6- weeks, however; some had a longer duration of response. The degree and pattern of muscle spasticity and overall clinical benefit at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. The safety and effectiveness of DYSPORT injected into proximal muscles of the lower limb for the treatment of spasticity in pediatric patients has not been established. Lower Limb Spasticity in Pediatric Patients less than years of age The safety and effectiveness of DYSPORT in the treatment of lower limb spasticity in pediatric patients of less than years of age has not been evaluated. Treatment of Upper Limb Spasticity in Pediatric Patients The safety and effectiveness of DYSPORT in the treatment of upper limb spasticity in pediatric patients has not been demonstrated [see Warnings and Precautions (5.)]. Instructions for Preparation and Administration for the Treatment of Lower Limb Spasticity in Pediatric Patients years and older DYSPORT is supplied as single-use Unit or 5Unit vials. Only use sterile preservative-free.9 Sodium Chloride Injection, USP for reconstitution of DYSPORT. Each 5 Unit vial of DYSPORT is to be reconstituted with.5 ml of preservative-free.9 Sodium Chloride Injection, USP prior to injection. Each Unit vial of DYSPORT is to be reconstituted with.5 ml of preservative-free.9 Sodium Chloride Injection, USP prior to injection. The concentration of the resulting solution will be Units per. ml. Further dilution with preservative-free.9 Sodium Chloride Injection, USP, may be required to achieve the final volume for injection. No more than.5 ml of DYSPORT should be administered in any single injection site. To calculate the total units of DYSPORT required for treatment of one leg, select the dose of DYSPORT in Units/kg/leg and the body weight (kg) of the patient (see Table 4). Using an appropriately sized sterile syringe (e.g., ml syringe), needle and aseptic technique, draw up.5 ml of preservative-free.9 Sodium Chloride Injection, USP. Insert the needle into the DYSPORT 5 Unit vial. The partial vacuum will begin to pull the saline into the vial. Any remaining required saline should be expressed into the vial manually. Do not use the vial if no vacuum is observed. Swirl gently to dissolve. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted DYSPORT should be a clear, colorless solution, free of particulate matter; otherwise it should not be injected. Draw the required patient dose of DYSPORT into a sterile syringe and dilute with additional preservative-free.9 Sodium Chloride Injection, USP, if required, to achieve the final volume for injection. Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach an appropriately sized new sterile needle. Use immediately after reconstitution in the syringe. Discard the vial and needle in accordance with local regulations. DOSAGE FORMS AND STRENGTHS For injection: Units or 5 Units of lyophilized powder in a single-use vial for reconstitution with preservative-free.9 Sodium Chloride Injection, USP. 4 CONTRAINDICATIONS DYSPORT is contraindicated in patients with: Known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see Description ()]. Hypersensitivity reactions have been reported, including anaphylaxis [see Adverse Reactions (6.)]. This product may contain trace amounts of cow s milk protein. Patients known to be allergic to cow s milk protein should not be treated with DYSPORT. Infection at the proposed injection site(s). 5 WARNINGS AND PRECAUTIONS 5. Lack of Interchangeability between Botulinum Toxin Products The potency Units of DYSPORT are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of DYSPORT cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method [see Description ()]. 5. Spread of Toxin Effect Post-marketing safety data from DYSPORT and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including upper limb spasticity in children and approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than the maximum recommended total dose [see Use in Specific Populations (8.4)]. 5. Dysphagia and Breathing Difficulties Treatment with DYSPORT and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant effects occur, additional respiratory muscles may be involved [see Warnings and Precautions (5.)]. Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several weeks, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised. Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure. Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Warnings and Precautions (5.), Adverse Reactions (6.), Clinical Pharmacology (.)]. 5.4 Facial Anatomy in the Treatment of Glabellar Lines Caution should be exercised when administering DYSPORT to patients with surgical alterations to the facial anatomy, excessive weakness or atrophy in the target muscle(s), marked facial asymmetry, inflammation at the injection site(s), ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin [see Dosage and Administration (.)] or the inability to substantially lessen glabellar lines by physically spreading them apart [see Clinical Studies (4.)].